1. Field of Invention
The present invention relates to a novel improved process for the preparation of 6-substituted penicillanic acids. More particularly, it relates to an improved process for the preparation of 6-[D(-)-.alpha.-(4-alkyl-2,3-dioxo-]-piperazinocarboxylamino)phenylacetami do]penicillanic acids of Formula (I) ##STR1## wherein R represents C.sub.1 -C.sub.4 alkyl. These compounds are useful as antibiotics for the treatment of pneumonia, peritonitis, and blood system infections.
2. Description of Prior Art
Saikawa et al. disclose in U.S. Pat. No. 4,112,090 a process for preparing 6-substituted penicillanic acids of formula (I) by reacting a 4-C.sub.1 -C.sub.4 alkyl-2,3-dioxo-1-piperazinocarbonyl chloride of Formula II ##STR2## wherein R is C.sub.1 -C.sub.4 alkyl, with 6-[D(-)-.alpha.-amino-phenylacetamido]penicillanic acid trihydrate, commonly known as ampicillin trihydrate, represented by Formula (III). ##STR3##
In Example 23 of this reference, a suspension of (III) in a mixture of 10 parts water and 4.5 parts by weight of ethyl acetate per part by weight of compound III is cooled to 2.degree. C., admixed with 2 molar equivalents of potassium carbonate at 2.degree.-3.degree. C. for several minutes, admixed with 1 molar proportion of a compound of formula (II) wherein R is methyl at 2.degree.-3.degree. C. over a period of 10 minutes, and further reacted at said temperature for 15 minutes. The reaction mixture is clarified to remove some insolubles and the mother liquor is mixed with an additional 18 parts by weight of ethyl acetate per part by weight of compound III originally charged. The resulting mixture is then acidified with 1 molar equivalent of 2N HCl at 20.degree.-22.degree. C. over a period of 5 minutes, and stirred at 20.degree.-22.degree. C. for 5 hours. The crystals which precipitate are collected, washed successively with water and isopropanol, and dried to obtain a dihydrate of 6-[D(-)-.alpha.-(4-methyl-2,3-dioxo-1-piperazinocarbonylimino)phenylacetam ido]penicillanic acid in a yield of 75.4%. In a similar example, a monohydrate of 6-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetami do]penicillanic acid is obtained in a yield of 84.8% with the compound of Formula (II) wherein R=ethyl.
There is a need for an improved process which significantly increases the yield obtained. The present invention provides such a process, with a final yield of about 95%.